Sitagliptin phosphate has a chemical name of 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-α]pyrazine phosphate, and the commercially medicine form is its monohydrate. The chemical structure thereof is shown as the following formula III:

Sitagliptin phosphate is the first orally-effective and selective DPP-IV inhibitor on the market, and is used for treating Type II diabetes by oral administration once a day. Since launched to the market in 2006, sitagliptin phosphate has already entered about 60 countries, and more than 15 million prescription drugs have been made all over the world. The Phase III clinical trials of sitagliptin on treating Type I diabetes are in process. The trade name of sitagliptin phosphate tablet produced by Merck is JANUVIA (Sitagliptin Phosphate).
(R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butanoic acid is one of the important intermediates for synthesizing sitagliptin, and the chemical structure thereof is shown as the following formula IV:

Based on comprehensive literature investigation, the inventors have found that the key step of synthesizing the compound of formula IV lies in constructing a chiral center of C3 attached to an amino group. Currently, the methods reported in the literatures are generally focusing on the step of preparing a proper substrate with trifluorophenylacetic acid as a start material and constructing a chiral center. There are mainly three methods: 1) separating racemates; 2) catalyzing a prochiral ketone with Ru-BINAP to obtain a chiral secondary alcohol, and reducing it after azidation; and 3) preparing an acyl-protected enamine, and subjecting it to asymmetric catalytic hydrogenation.

The main problems of this method are that:
1) in the reduction of the fourth step, the reaction starts only after borane is produced by catalyzing sodium borohydride with sulfuric acid; however, the use of sulfuric acid would increase the discharge of “three-waste” (waste gas, waste water and waste residues); further, borane gas is highly toxic, rendering potential safety risks; and
2) in the fifth step, a separation is required to obtain G, with a yield of about 31%; the yield is low, the economic efficiency is poor, and thus the production cost is significantly increased.

The main problems of this method are that:
1) in the reduction of the third step, the used (R)-Me-CBS catalyst is expensive, the borane reagent is highly toxic, and the enzyme is difficult to obtain;
2) in the fourth step, an azide is required, rendering large potential safety risks in scale-up production; and
3) seven steps of reactions are required to prepare compound IV, which is a long route.

The isomer purity in this method is low, and the yield is only 41%. Although 24% start materials can be recovered from the mother liquor, the cost and energy consumption is too high for industrial production.
The reaction route described in PCT Publication WO2010078440 is as follows:

The main problems of this method are that: the asymmetric reduction proceeds only after the amino group of the enamine produced from the second step is protected. It is reported that the step of protecting the enamine results in a low yield.